Epilepsy is a chronic disease characterized by recurrent convulsions without an apparent cause. These convulsions are transient and occur as a consequence of an excessive or synchronous neuronal activity of the brain. However, by extension, the term “epilepsy” includes a set of diseases characterized by a wide variety of symptoms, an abnormal episodic electrical activity in the brain which causes convulsions being common to all of them.
The medicaments currently used for the prevention and/or treatment of epilepsy (antiepileptics) are fundamentally based on (voltage and neuronal receptor-associated) ion channel inhibitor compounds; however, the use of such drugs causes serious side effects in the patients which affect the central nervous system such as ataxia, diplopia (double vision), motor incoordination, hyperactivity, etc., therefore it is necessary to develop new compounds useful for the treatment of epilepsy. Advantageously, the safety and efficacy of said compounds must be equal to or greater than those of the antiepileptics normally used in the treatment of epilepsy.
It has now been found that statins can be used as anticonvulsant and antiepileptic agents in the prevention and/or treatment of epilepsy, epileptic seizures and convulsions.
Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme which catalyzes the limiting step in cholesterol biosynthesis, and are normally used to reduce the high cholesterol levels associated with low-density lipoproteins (LDL).
The therapeutic indications of statins have been expanding over the years. In fact, these compounds are not solely used to reduce cholesterol and triglycerides levels but also used to reduce the risk of myocardial infarction and coronary death. Furthermore, new properties are being associated with statins, especially at the level of brain damage caused by trauma or in dementias. Antioxidant and anti-inflammatory properties have been proposed (Pahan, Cell Mol Life Sci. 2006; 63[10]:1165-78). Additionally, it has been demonstrated that simvastatin intensifies the memory and learning capacity in mice (Ling et al., Ann Neurol. 2006; 60[6]:729-39). Likewise, the potential use thereof as an antineoplastic agent and antiretroviral agent has been described. It has also been described that some statins prevent neuronal damage in models of acute diseases such as retinal degeneration (Nakazawa et al., J Neurochem. 2007; 100[4]:1018-31) and in trauma or ischemia (Vaughan and Delanty, Stroke 1999; 30[9]:1969-73) as well as in in vitro models of primary cortical neurons (Bosel et al., J Neurochem. 2005; 92[6]:1386-98; Zacco et al. J Neurosci. 2003; 23[35]:11104-11).
Statins are generally drugs with a high safety level as administered to reduce cholesterol and triglycerides levels in very wide pockets of the population. In fact, drugs related to the control of cholesterol and triglycerides levels represent the most successful therapeutic area worldwide, where statins represent 90% thereof, the 2 most sold drugs during the last 2 years being atorvastatin and simvastatin. Nevertheless, some statins have been withdrawn from the market as a consequence of their side effects. Thus, epileptic seizures have been documented in some cases after the administration of statins, specifically, an episode of severe rhabdomyolysis with convulsions and coma after the administration of rosuvastatin to a patient has been documented (Lorenzoni et al., Arq Neuropsiquiatr. 2007; 65[3B]:834-7); and, in another case, the administration of fluvastatin to a patient with catastrophic antiphospholipid syndrome caused focal convulsions (Miesbach et al., J Neurol Sci. 2005; 238[1-2]:93-5).